Vasoactive intestinal peptide (VIP) was first discovered, isolated and purified from porcine intestines. U.S. Pat. No. 4,119,110. The peptide has twenty-eight (28) amino acids and has extensive homology to secretin and glucagon. Carlquist, M. et al., Horm. Metabol. Res., 14, 28-29 [1982]. The amino acid sequence of VIP is as follows: ##STR1##
VIP is known to exhibit a wide range of biological activities throughout the gastrointestinal tract and circulatory system. In light of its similarity to gastrointestinal hormones, VIP has been found to stimulate pancreatic and biliary secretion, hepatic glycogenolysis, glucagon and insulin secretion and to activate weakly pancreatic bicarbonate release. Kerrins, C. and Said, S. I., Proc. Soc. Exp. Biol. Med., 142, 1014-1017 (1972), Domschke, S., et al. Gastroenterology, 73, 478-480 (1977).
Neurons containing VIP have been localized by immunoassay in cells of the endocrine and exocrine systems, intestine and smooth muscle. Polak, J. M. et al. Gut, 15, 720-724 (1974). VIP has been found to be a neuroeffector causing the release of several hormones including prolactin (Frawley, L. S., et al., Neuroendocrinology 33; 79-83 (1981)), thyroxine (Ahren, B. et al., Nature, Lond. 287; 343-345 (1980)), and insulin and glucagon Schebalin, M. et al., Am. J. Physiol. E. 232; 197-200 (1977). VIP was also found to stimulate renin release from the kidney in vivo and in vitro. Porter, J. P. et al., Neuroendocrinology 36; 404-408 (1983). VIP has subsequently been found to be present in nerves and nerve terminals in the airways of various animal species and man. Dey, R. D. and Said, S. I. Fed. Proc. 39, 1962 (1980), Said, S. I., Kitamura, S., Yoshida, T., Preskitt, J., and Holden, L. D., Ann. N.Y. Acad. Sciences 221, 103-114, (1974). VIP's cardiovascular and bronchopulmonary effects are of interest as VIP has been found to be a powerful vasodilator and potent smooth muscle relaxant, acting on peripheral, pulmonary, and coronary vascular beds, Said, S. I., et al. Clin. Res. 20, 29 (1972). VIP has recently been found to have a vasodilatory effect on cerebral blood vessels. Lee, T. J. and Berczin, I., Science, 224, 898-900 (1984). In vitro studies demonstrated that exogenously applied vasoactive intestinal peptide to cerebral arteries induced vasodilation suggesting VIP as a possible transmitter for cerebral dilation. Lee, T. and Saito, A., Science 224, 898-901 (1984).
VIP has also been found to relax smooth muscle. Since it is normally present in airway tissues, as noted above, it is hypothesized that it may be an endogenous promotor of bronchial smooth muscle relaxation. Dey, R. D. and Said, S. I., Fed. Proc., 39, 1962 (1980). In vitro and in vivo testing have shown VIP to relax tracheal smooth muscle and protect against bronchoconstrictor agents such as histamine and prostaglandin F.sub.2.alpha.. Wasserman, M. A. et al. in Vasoactive Intestinal Peptide, ed, S. I. Said, 177-184, Raven Press, N.Y. 1982, Said, S. I. et al. Ann. N.Y. Acad. Sci. 221, 103-114 (1974). VIP, when given intravenously, has been found to protect against bronchoconstrictor agents such as histamine, prostaglandin F.sub.2.alpha., leukotriene, platelet activating factor as well as antigen-induced bronchoconstrictions. Said, S. I. et al., supra, 1982. However, when given by intravenous administration there are also cardiovascular effects including tachycardia and hypotension, not acceptable for use as a pharmaceutical. VIP, substituted at position 8 with glutamic acid in place of aspartic acid, was found to be less potent than VIP in effecting pancreatic secretion. Takeyama et al., Chem. Pharm. Bull., 28(7), 2265 (1980). No other amino acid substitutions in the VIP molecule have been disclosed in the prior art.
VIP when administered by aerosol to humans has been somewhat inconsistent in ameliorating histamine bronchoconstriction. Altieri et al., Pharmacologist, 25, 123 (1983). VIP given by inhalation to humans was found to have no significant effect on baseline airway function but did have a protective effect against histamine-induced bronchoconstriction. Barnes, P. J. and Dixon, C. M. S., Rev. Resp. Dis. 130; 162-166 (1984). VIP when given by aerosol displayed no tachycardia or hypotensive effects in conjunction with the bronchodilation. Said, S. I. et al., in Vasoactive Intestinal Peptides, edited by S. I. Said, pp. 185-191, Raven Press, N.Y., 1982. In addition, VIP has failed to relax bronchial smooth muscle in in vitro experiments, Davis et al. 1982.